Differential IL-12 responsiveness of T cells but not of NK cells from tumor-bearing mice in IL-12-responsive versus -unresponsive tumor models

While IL-12 administration induces tumor regression through stimulating T cells in tumor-bearing mice, this IL-12 effect is observed in some but not all tumor models. The present study aimed to compare IL-12 responsiveness of T cells from tumor-bearing mice in IL-12-responsive (CSA1M and OV-HM) and -unresponsive (Meth A) tumor models. Tumor regression in IL-12-responsive tumor models required the participation of T cells, but not of NK1.1(+) cells. Because a NK1.1(+) cell population was the major producer of IFN-gamma, comparable levels of IFN-gamma production were induced in IL-12-responsive and -unresponsive tumor-bearing mice. This indicates that the amount of IFN-gamma produced in tumor-bearing individuals does not correlate with the anti-tumor efficacy of IL-12. In contrast, IL-12 responsiveness of T cells differed between the responsive and unresponsive models: purified T cells from CSA1M/OV-HM-bearing or Meth A-bearing mice exhibited high or low IL-12 responsiveness respectively, when evaluated by the amounts of IFN-gamma produced in response to IL-12. T cells from CSA1M- or OV-HM-bearing but not from Meth A-bearing mice exhibited enhanced levels of mRNA for the IL-12 receptor (IL-12R). These results indicate that a fundamental difference exists in IL-12 responsiveness of T cells between IL-12-responsive and -unresponsive tumor models, and that such a difference is associated with the expression of IL-12R on T cells.     

Two Methods for Identifying Wiener Cascades Having Noninvertible Static Nonlinearities

Two methods are proposed for identifying the component elements of a Wiener cascade that is comprised of a dynamic linear element (L) followed by a static nonlinearity (N). Both methods avoid potential problems of instability in a procedure presented by Paulin [M. G. Paulin, Biol. Cybern. 69: 67–76, 1993], which itself is a modification of a method described earlier by Hunter and Korenberg [I. W. Hunter and M. J. Korenberg, Biol. Cybern. 55: 135–144, 1996]. The latter method is a rapidly convergent iterative procedure that produces accurate estimates of the L and N elements from short data records, provided that the static nonlinearity N is invertible. Subsequently, Paulin introduced a modification that removed this limitation and enabled identification of Wiener cascades with nonmonotonic static nonlinearities. However, Paulin presented his modification employing an autoregressive moving average (ARMA) model representation for the dynamic linear element. To remove the possibility that the estimated ARMA model could be unstable, we recast the procedure by utilizing instead a rapid method for finding an impulse response representation for the dynamic linear element. However, in this form the procedure did not have good convergence properties, so we introduced two key ideas, both of which provide effective alternatives for identifying Wiener cascades whether or not the static nonlinearities therein are invertible. The new procedures are illustrated on challenging examples involving high-degree polynomial static nonlinearities, of odd or even symmetry, a high-pass linear element, and output noise corruption of 50%. © 1999 Biomedical Engineering Society. PAC99: 8710+e, 0210Nj, 0250-r     

The Heritability of Depression Symptoms in Elderly Danish Twins: Occasion-Specific Versus General Effects

Depression symptomatology was assessed up to four times at 2-year intervals on a sample of 2100 Danish twins initially aged 70 years and older. Data were analyzed using the biometric growth model approach proposed by Neale and McArdle (2000). Results show that occasion-specific depression is moderately and equally heritable in men and women (occasion-specific estimates of heritability ranged from 22% to 37%). Estimates of phenotypic variance, genetic variance, and heritability did not vary systematically across waves. In the best-fitting growth model, depression symptomatology was accounted for by two factors: (1) a level (i.e., average) effect that was highly heritable (estimate of 69% in women and 64% in men) and reflected overall vulnerability, and (2) a residual effect that was nonheritable and reflected occasion-specific circumstances that could either exacerbate or moderate inherited vulnerability. Attempts to identify specific genetic contributions to depression might profitably focus on average levels across multiple assessments, while attempts to identify specific environmental effects might profitably focus on deviations about this average.     

Ocular pharmacokinetic models of clonidine-3H hydrochloride

A single topical instillation of clonidine-³H HCl solution (0.2%) was administered to the rabbit eye (30 μl) in order to study the drug's ocular pharmacokinetics. Seven different tissues and plasma were excised and assayed for drug over 180min. By 45–60 min pseudoequilibrium is reached for the cornea, iris/ciliary body, and aqueous humor. Thereafter, drug levels in these tissues decline in parallel. The data are fit separately to a physiological model and a classical diffusion model for which seven ocular tissue compartments and a plasma reservoir are constructed for each model. Clearance terms and distribution equilibrium coefficients are determined from the tissue level data and used as parameters in fitting the mass balance differential equations representing the physiological model. The model parameters can also be fit to a 0.4% single dose. In a separate experiment, a topical infusion technique was designed to provide a constant rate input to the cornea until an apparent steady state was reached in aqueous humor at 55 min. Aqueous humor levels were assayed for clonidine over the infusion and postinfusion periods. The physiological model parameters are fit to the topical infusion data and show good agreement between the predicted and experimental data. The classical model is too complex to fit the data to integrated exponential equations primarily because the method of residuals is inadequate in determining a sufficient set of initial estimates. This is overcome by dividing the eight-compartment model into seven fragmental models, each representing one to five compartments. A stepwise procedure is developed in which initial estimates are obtained for each separate fragmental model and refined. The refined parameter values can then be used as initial estimates for the complex model. Differential equations for the complex model are fit simultaneously to tissue levels representing each compartment. By observation, the classical model fit the data more closely than the physiological model. Statistical moment theory is also applied to the topical infusion data to determine ocular pharmacokinetic parameters for clonidine. The calculated values are: corneal absorption rate constantk _a , 0.00139 min^?1; aqueous humor elimination rate constantk ₁₀ , 0.0658min^?1; mean residence timeMRT _d , 35.6 min; apparent steadystate volume of distributionV _ss, 0.530 ml; and ocular clearanceQ _e , 14.9 =μl/min. The fraction absorbed from the single instillation is estimated as 0.0163.     

Effect of administration of diethylcarbamazine with and without fluconazole on experimental fungal infections in mice

Other researchers have found that diethylcarbamazine (DEC) is effective treatment for filariasis despite a lack of demonstrated in vitro antifilarial activity. The results of our previous investigations using feline and murine leukemia virus models encouraged us to investigate the use of DEC with other infections. In our current experiments, DEC treatment was associated with lower brain fungal burden in fluconazole-treated mice following intravenous injection of Aspergillus fumigatus or increasing numbers of Cryptococcus neoformans organisms, and lower brain and kidney levels of Candida albicans following intravenous injection of increasing numbers of C. albicans. Further investigation of combined DEC and fluconazole treatment of fungal infections is warranted.     

Ⅱ型糖尿病并发心脏病危险因素的logistic回归分析

探讨Ⅱ型糖尿病并发心脏病的危险因素,用ｌｏｇｉｓｔｉｃ回归模型对糖尿病并发心脏病的危险因素进行分析,结果显示患者体重指数较大、心理评分较高、舒张压高及血脂高,其发生心脏病的风险增加;饮食评分较高,较好的控制饮食,其并发心脏病的风险较低。故较好的控制患者血压、血脂和饮食可以减少并发症的发生、延长患者的寿命 。     

肉毒碱治疗TPN大鼠肝脂肪变性的研究

目的 探讨在全胃肠外营养（ＴＰＮ）中补充肉毒碱减轻肝脂肪变性的作用。方法 １８只正常Ｗｉｓｔａｒ大鼠和１９只肝硬化Ｗｉｓｔａｒ大鼠分别随机分为６组,Ａ１组、Ａ２组,自由进食和进水（各６只）;Ｂ１组、Ｂ２组,ＴＰＮ（分别６只、７只）;Ｃ１组、 ,ＴＰＮ加肉毒碱（各６只）。各组实验结束后测肝功能,肝脂肪及行肝脏的组织学检查。结果 ＴＰＮ组肝内脂肪显著２,ＴＰＮ＋肉毒碱组肝内脂肪明显减少。结论 在ＴＰＮ     

多脏器微栓塞病细胞综合征动物实验模型──定义、判断标准、发生机制及其与临床的关系

利用健康杂交犬制作了多脏器微栓塞病细胞综合征（ＰＯＭＳ）模型,观察在不同时限、不同组织器官造成的病理生理改变。从中发现,钳夹腹主动脉阻断血流后,其供血器官都发生了ＲＯＭＳ,且不同器官的功能与结构损害有发生时间和程度的不同,但均有不同程度的微栓塞形成趋势,这有助对“多脏器衰竭”概念认识的深化。     

Hybrid Pharmacokinetic Models to Describe Anti-HIV Nucleoside Brain Disposition Following Parent and Prodrug Administration in Mice

Brain delivery of active anti-HIV compounds is important for successful treatment of the AIDS patient. As an initial step in predicting human brain drug concentrations, hybrid pharmacokinetic models were developed to characterize the disposition of anti-HIV nucleosides following parent and prodrug administrations in mice. Mouse data were obtained following intravenous administration of 3-azido-2,3-dideoxyuridine (AZddU or AZDU), 3-azido-3-deoxythymidine (AZT), and their dihydropyridine prodrugs (AZddU-DHP and AZT-DHP). Exponential equations were fitted to the serum concentration–time data for each species, including the pyridinium ion moieties, and subsequently used in differential mass balance equations describing the brain dynamics of each compound. Model parameters for the mass balance equations were estimated by various techniques, including the utilization of in vitro data. In general, model-predicted brain concentrations agreed with the observed data. Similar data in larger animals will permit scale-up of the current model to predict human brain drug concentrations.     

Kinematic models and human elbow flexion movements: Quantitative analysis

Summary The smoothness with which movements are customarily performed has led Hogan (1984) to formulate a model for trajectory planning by the central nervous system in which the goal is to maximize smoothness, one measure of which is the integrated mean squared magnitude of jerk (jerk cost). We tested the applicability of this minimum-jerk model to one-joint goal directed movements performed by human subjects at different speeds and amplitudes, by comparing kinematic parameters and the jerk cost predicted by the mathematical model with values calculated from experimental data. We also tested a higher order, minimum-snap kinematic model. Normal subjects performed elbow flexions of 5 to 50 degrees as rapidly and accurately as possible and also at slower speeds. The boundary conditions of both models were adjusted to account for the failure of subjects to produce movements which reached equilibrium precisely at the target (so that acceleration and velocity reached zero together). Typically, fast movements (< 300 ms duration) were fairly symmetric in that the durations and amplitudes of acceleration and deceleration were approximately equal; slower movements (> 300ms) were asymmetric with strong, brief acceleration peaks and broad, slow deceleration peaks. In fast movements, the calculated jerk cost was consistently higher than predicted by the minimum-jerk model; a good fit to all kinematic parameters was provided by the minimum-snap model (a seventh-order polynomial). Neither model consistently predicted the trajectories of slower movements. We conclude that muscle/limb dynamics can account for the success of the minimum-snap model with fast movements, and that there is no evidence of planning for maximal smoothness in slower movements.